Summary Racial disparities in colorectal cancer (CRC) have been well documented and are widening. Increasing data strongly suggest that neighborhood socioeconomic disparities contribute to racial/ethnic health disparities across a variety of health outcomes above and beyond individual-level risk factors. How neighborhood social and structural disadvantages may modulate an individual's risk, and the molecular mechanisms by which these multiple-level risk factors may act upon to drive the development of colon neoplasia are largely unexplored. We propose an innovative epigenetic epidemiology study to comprehensively examine the complex interplay of neighborhood-level socioeconomic status, individual-level risk factors, and epigenetic age acceleration of normal colonic tissues in racial disparities and the development early colon neoplasia. Our central hypothesis is that colonic tissue epigenetic age acceleration, assessed by genome-wide DNA methylation, mediates the race- differential colon carcinogenic effects of individual-level CRC risk factors. We further hypothesize that neighborhood disadvantage in part accounts for racial disparities in the association of known individual-level CRC risk factors and risk of early colon neoplasia. Our proposal capitalizes upon a unique resource established as part of the parent Cleveland Colon Screening and Risk Factors Cohort Study where extensive epidemiological data and normal colonic tissues have been collected from 928 (367 African Americans, 561 Caucasians) patients (436 adenoma cases and 492 adenoma-free controls) undergoing colon screening. By cross-linking the cohort to the NEO CANDO (NorthEast Ohio Community and Neighborhood Data for Organizing) database that contains over 20 years of indicators on social, economic and physical conditions in the region's communities, we will use various census tract-based neighborhood socioeconomic data to assess neighborhood disadvantage for the current proposal. We will first examine the effect of race and individual-level risk factors on colon specific epigenetic age acceleration (Aims 1 and 2). We will then investigate the effect of upstream neighborhood contextual factors on epigenetic age acceleration above and beyond individual-level risk factors (Aim 3). Last, we will use a structural equation modeling approach to synthesize the information of neighborhood disadvantage and individual-level risk factors and evaluate both the direct and indirect (i.e., mediated by epigenetic age acceleration) effects on risk of colon adenoma (Aim 4). Our study will provide novel insight of how neighborhood disadvantage and individual lifestyle may accelerate epigenetic aging of colon and drive racial disparities in the development of early colon neoplasia. Our results will have significant implication for developing effective primary prevention strategy to reduce racial disparities in colon neoplasia.